This invention pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent is a 5-halopyrimidin-2-yl moiety and the other is a carbon chain bearing a carbocycle or heterocycle moiety at its terminus, usually via a linking hetero atom or functional group moiety.
Related art may be viewed in light of the following general structural Formula 1. ##STR1## in which Ar is an aromatic ring, usually phenyl; X is a carbonyl or carbinol group; alk is an alkylene chain.
The most closely related art would appear to be U.S. Pat. No. 4,605,655, issued to Yevich, et al., on Aug. 12, 1986. This patent disclosed and claimed piperazinylbutyrophenone derivatives possessing neuroleptic properties and characterized by structural Formula 2. ##STR2## wherein X is ##STR3## With R being C.sub.1-4 alkyl, hydrogen or fluorophenyl; and Y is hydrogen or halogen. The instant anti-ischemic compounds are distinguished from these art compounds either by the nature of the terminal carbocyclic ring system, the nature of X, the presence of an alkylene bridge on the piperazine ring and the nature of the R.sup.3 substituent.
In U.S. Pat. No. 2,973,360, issued Feb. 28, 1961, a series of CNS depressant compounds is disclosed with Ar being 2-thienyl; X being carbonyl or carbinol; and alk being C.sub.2 and C.sub.3 alkylene. The most pertinent compound specifically exemplified and claimed in this patent is shown below as structure (3). ##STR4##
The following references, while related, are felt to be less relevant to the new compounds disclosed in this application.
Reginer, et al., U.S. Pat. No. 3,299,067, issued Jan. 17, 1967 discloses compounds comprising a benzyl-type moiety attached to the 2-pyrimidinylpiperazine. A specific example of this series which is said to be useful as peripheral vasodilators, analgesics and antiinflammatory agents, is shown below as structure (4). ##STR5## U.S. Pat. No. 3,802,210 issued to Regnier, et al., in April 1974 relates to a series of aryloxypropanolamine antihypertensive compounds having a pyrimidinylpiperazine moiety as in (5). However, these compounds are not butyrophenones or close analogs. ##STR6##
U.S. Pat. No. 4,316,899 issued to Markwell on Feb. 23, 1982 relates to another series of aryloxypropanolamine antihypertensive compounds containing a pyrimidinylpiperazine moiety as exemplified by structure (6) ##STR7##
Gotti, et al., JPET, 247/3, pages 1211-1221 (1988); have disclosed that ifenprodil and a derivative are effective in tissue sparing in animal models of stroke and brain infarction. ##STR8##
Wauquier, et al., in "Drug Development Research", 8/373-380 (1986) disclosed that Sabeluzole (R 58,735) is a potent antihypoxic agent with anticonvulsant properties. ##STR9##
A series of anti-anoxic 2-[4-benzoyl-1-piperidinyl)-1-phenylalkanol derivatives, having some structural resemblance to ifenprodil type compounds, is disclosed in U.S. Pat. No. 4,711,899 issued in December, 1987 to Gaudilliere, et al.
There is nothing in these references, or in the general prior art, to suggest the anti-ischemic compounds of the present invention.